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Università di Padova
Dipartimento di Medicina (DIMED)
Allergologia ed Immunologia Clinica
Le interstiziopatie polmonari
Nuove prospettive terapeutiche
Carlo Agostini
Disclosure
In relation to this presentation, I declare the following, real or perceived conflicts of interest:
• C.A. participated in advisory board meetings for Intermune, Inc, Roche, Inc, CSL Behring
GmbH, Inc, Baxter Int, Inc, LFB, Inc, Baxalta Int, Inc, Novartis, Inc
• C.A. received consultancy fees from Intermune, Inc, Baxter Int., Boehringer Ingelheim,
Centocor, Inc, Baxalta Int, Inc
• C.A. received travel grants from CSL Behring GmbH, Inc, Boehringer Ingelheim,
Intermune/Roche, Inc, Baxalta Int, Inc
• His institution (Dipartimento di Medicina) received grants from Intermune/Roche, Inc, CSL
Behring GmbH, Inc, Baxter International, Inc, Boehringer Ingelheim, Actelion, Inc, Gilead,
Inc, Janssen Phar. Comp.
• No other fees or grants relevant to this lecture are reported
Internal Medicine - Allergy Clinical Immunology Department of Medicine – DIMEDCentre for Immune Mediated Rare Diseases
Diagnosis and treatment of immunological and allergic
diseases, including patients with primary and
secondary immunodeficiency, autoimmune diseases,
autoinflammatory disorders, immunomediated and
other rare interstitial lung diseases, including
sarcoidosis
Venetian Institute
of Molecular Medicine
Identification of potential
therapeutic targets
in immune mediated and
allergic disorders
Carlo Agostini
Padua University Hospital
MALATTIA RARA POLMONARE PREVALENZA (PER 100.000) INCIDENZA
DEFICIT ALFA-1 ANTITRIPSINA 33 1:2.500
FIBROSI POLMONARE IDIOPATICA 30 1:4.500
SCLEROSI SISTEMICA 26 1:6.300
IPERTENSIONE ARTERIOSA POLMONARE 19.5 1:6.300
DERMATOMIOSITE-POLIMIOSITE 17 1:6.500
RENDU-OSLER 16 1:6.500
SARCOIDOSI 15 1:6.500
DISPLASIA BRONCOPOLMONARE 13 1:6.500
FIBROSI CISTICA 12.6 1:8.000
CARCINOMA POLMONARE (PICCOLE CELLULE) 11.2 1:8.000
GRANULOMATOSi CON POLIANGIOITE 6.6 1:10.000
IMMUNODEFICIENZA COMUNE VARIABILE 4 1:25.000
SINDROME IPEREOSINOFILA 1.5 1:60.000
GRANULOMATOSi EOSINOFILA CON POLIANGITE 1 1:100.000
LINFANGIOLEIOMIOMATOSI 0.56 1:200.000
ISTIOCITOSI A CELLULE DI LANGERHANS 0.2 1.500.000
PROTEINOSI ALVEOLARE 0.1 1:1.000.000
Prevalenza stimata in Europa delle principali malattie rare polmonari(dati Orphanet)
Lancet Respir Med 2013; 1: 479–87
Incidence and Prevalence of Idiopathic Pulmonary Fibrosis
a large United States' health plan
3 million 18 yr or older persons in total residing in 20 states
1,943 had one or more diagnoses of IPF at any time during a 5-yr period of observation
prevalence of IPF was estimated to range from 4.0 per 100,000 persons aged 18 to 34 yr to 227.2 per 100,000 among those aged 75 yr or older
considerando una popolazione di 60 milioni di individui la stima è di circa 19.000 malati di IPF
IPF: An Italian real life study
AGE CLASS
< 60 anni 13.3%
61-65 anni 15.6%
> 65 anni 71.1%
9,3 nuovi casi all'anno ogni 100.000 persone
Harari S. et al. Respiration 2015, dx.doi.org/10.1016/j.rmed.2015.04.010
Idiopathic Pulmonary Fibrosis Not Aging CouldBe Causing Breathlessness
Ridotta sopravvivenza
• immunodeficienza combinata grave• fibrosi polmonare idiopatica• ipertensione arteriosa polmonare• linfangioleiomiomatosi• graft-versus-host disease• dermatomiosite-polimiosite• mesotelioma• ca. polmonare a piccole cellule
Lungasopravvivenza
• deficit alfa-1 antitripsina• alcune vasculiti• malattie del connettivo• fibrosi cistica• proteinosi alveolare• sarcoidosi• immunodeficienza comune
variabile
Malattie rare polmonari e prognosi
a-SMA
IPF
Natural History of Idiopathic Pulmonary Fibrosis
Bottlenecks between research and developmentof therapies for rare diseases
part of the research and development process is the ‘translation gap’ where there is no obvious funding body
2012 EUCERD Report on the State of the Art of Rare Disease Activities in Europe
Clinical Trials in IPF
TWO PATHWAYS TO PULMONARY
FIBROSIS
Epithelial cell
injury& activation
interstitium
ALVEOLAR
SPACE
Inflammation
epithelium
endothelium
VASCULAR
SPACE
FIBROTIC PHASE
persistence of
etiologic agent
genetic
backgroundFibrotic
phase
fibroblastsIL-13
TGFb
PDGFb
Lymphocyte Th2
IL-4
Agostini et al. Blood 93: 1277-1286 (1996)
PROTEOMEprotein content
The Omes Revolution
TRANSCRIPTOMERNA content
GENOMEDNA information
METABOLOMEmetabolites
Idiopathic
pulmonary fibrosis
MHC
CD4 and CD8 activated T cells
Chemokines/Receptors
Adhesion molecules
Interleukins/Receptors
Myofibroblasts
Cell proliferation
Epithelial activation
Tissue remodeling
Selman M et al. AJCCM
DOI: 10.1164/rccm.200504-644OC
Pulmonary Fibrosis in
HP
Old Concept
Cellular Inflammation
(Alveolitis/DIP)
Fibroblast Proliferation
Fibrosis (Collagen)
New Concept
Epithelial-Fibroblast
Pathway
(fibroblastic foci)
± Interstitial Inflammation
Fibrosis (Collagen)
Epithelial
transition
TWO PATHWAYS TO IDIOPATHIC
PULMONARY FIBROSIS
IPF: Survival in the 2000-2009 EraTransplant Recipents Excluded
Till 2011
Prednisone + AZA + NAC
=
the therapeutic standard in IPF
Not supported by placebo controlled study
PANTHER trial
Avoiding use of steroids,
immunosuppressants and
antioxidants
a simple way to improve
patients survival…
First lesson
Clinical Trials in IPF
End of the death valley
Since 2014 pirfenidone
EMT
MigrationProliferation
Growth factors
FibroblastsMyofibroblasts
TGF-beta
Th2-like factors
CXCL12
Fibrocytes
Wound clot
Procoagulant factors and PDGF
MMPs
PDGF-R
Noble, Lancet 2011;377:1760
FVC decline
Grouped analysis
% patients with ΔFVC > 10%
2403 mg Placebo P
21% 31% 0.003
• Progression free survival
RR=0.74 P=0.025
• Distance 6MWT
Δ=24m P=0.009
• Positive trend for mortality
reduction
• EMEA Approval
• AIFA Approval
The pirfenidone lessons
• A drug that works in the bleomycin model
can work in humans
• A trial of a drug can be positive in IPF
• A drug without a definitive molecular target
may work
• An IPF drug is approved by EMEA and
consequently by AIFA and FDA (october 2014)
24 october 2014
CHMP recommends label update for Esbriet
in idiopathic pulmonary fibrosis (IPF),
strengthening mortality benefit and
reinforcing safety profile
• slows the progression in patients with early disease
• even if there is progression in terms of FVC% (>10%)
mantains its efficacy both in terms of function and
survival during the following 6 months
Esbriet appears beneficial accross of IPF patients enrolled in different trials
Pirfenidone and moderate severe disease: An Italian real life study
In our national experience,
pirfenidone reduces the
rate of annual FVC decline
and provides significant
treatment benefit for
patients with moderate-
severe disease, suggesting
that the drug may also be
effective in patients with
more advanced disease
Harari S. et al. Respiratory Medicine 2015 DOI:
http://dx.doi.org/10.1016/j.rmed.2015.04.010
April 7 2016 nintedanib
Growth factors bind to receptors
How does nintedanibwork?
Signalling pathways inhibited
Nintedanib
indolidone derived drug
able to inhibit
neoangiogenesis
OFEV (NINTEDANIB)
Hilberg, Cancer Res 2008
Triple angiokinase
Inhibitor
Involved in IPF
pathogenesis
Nintedanib is a multi-target Tyrosine Kinase (TK) inhibitor
EMT
MigrationProliferation
Growth factors
FibroblastsMyofibroblasts
TGF-beta
Th2-like factors
CXCL12
Fibrocytes
Wound clot
Procoagulant factors and
PDGF
MMPs
PDGF-R
Signal blocker
The primary end point was the annual rate of decline in forced vital capacity (FVC) Key secondary end points were over a 52-week period•the time to the first acute exacerbation• the change from baseline in the total score on the St. George’s Respiratory Questionnaire
Main Results of INPULSIS-1 and INPULSIS-2
a) Nintedanib reduces the decline in FVC, which is
consistent with a slowing of disease progression;
b) Difference between the nintedanib and placebo
groups in the time to the first acute exacerbation
and quality of life (SGRQ) are not clear due to
the result differences between the 2 trials
c) Nintedanib is frequently associated with diarrhea,
which led to discontinuation of the study
medication in less than 5% of patients
• the FVC% baseline value, the presence of emphysema, the degreeof honeycombing at HTCT do not affect the rate of diseaseprogression of the size of nintedanib effect
• the FVC% values do affect the rate of acute exacerbations
Nintedanib 150 mg bid on slowing disease progression wasmainained up to 76 weeks
Key Points: Using Pirfenidone or Nintedanib?
Key Points: Several Unanswered Questions
MonotherapyCombination
therapyor
I am sure you will ask
Ongoing Clinical Trials with Biologicals in IPF
persistence of
etiologic agent
genetic
background
Fibrotic
phase
fibroblastsIL-13
TGFb
PDGFb
Lymphocyte Th2
IL-4
Agostini et al. Blood 93: 1277-1286 (1996)
PADOVA Allergology and Clinical Immunology Study Group
DEPARMENT OF MEDICINE & VENETIAN INSTITUTE OF MOLECULAR MEDICINE
Carlo Agostini
Francesco CinettoMonica Facco
Nicolò CompagnoRiccardo ScarpaGiacomo MalipieroMarcus KuhnSperanza Di MaggioStefania CelesteMaddalena MarconatoIlaria LazzaratoFrancesca RizzoAnna KuzenkoSandra Iannacone
Elisa Boscaro
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